Bcr/Abl is a chimeric oncogene implicated in the pathogenesis of Philadelphia chromosome (PH1) positive human leukemias. Worldwide there are approximately 60,000 patients with the Bcr/Abl translocation, with very limited therapy available. Bone marrow transplantation is the only treatment that results in long term survival. However, it is effective for only a subset of patients and is extremely expensive. Recent data have identified a protein termed GRB2 as a direct effector of Bcr/Abl. In turn, GRB2 may mediate oncogenic transformation by constitutive activation of the normal Ras protein. The applicant propose to develop a cell based assay for the detection of modulators of the Bcr/Abl-GRB2 complex. For this purpose Bcr/Abl and GRB2-specific antibodies will be paired to format a capture assay to detect compounds that disrupt the Bcr/Abl-GRB2 complex. In Phase I, the capture assay will be formatted from a bench assay into a cell based screen compatible with our automated screening. A pilot screen of 1000 fungal extracts will be carried out to test screen/extract compatibility and reproducibility of the assay in an automated format. In Phase II, Dr. Stam proposes to screen over 100,000 fungal extracts. Over the last 6 years Oncogene Science has developed a proprietary, state-of-the-art, high-throughput screening technology. This unique primary screening system employs live cells and robotic systems with a screening capacity in excess of 150,000 assays per week. This technology is ideally suited to the proposed search for such a modulator. Complete automation not only allows the primary screen to be cost-effective, but has proved essential to obtain highly reproducible data from a cell-based high-throughput screen.